ABTC-0904: targeting glioma stem cells in GBM: a phase 0/II study of hedgehog pathway inhibitor GDC-0449.
ABTC-0904: targeting glioma stem cells in GBM: a phase 0/II study of hedgehog pathway inhibitor GDC-0449.
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ABTC-0904：靶向 GBM 中的神经胶质瘤干细胞：hedgehog 通路抑制剂 GDC-0449 的 0/II 期研究。
DOI：
10.1007/s11060-022-04193-3
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发表时间：
2023
影响因子：
3.9
通讯作者：
Grossman,
中科院分区：
文献类型：
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作者：
Sloan,AndrewE;Nock,CharlesJ;Ye,Xiaobu;Buerki,Robert;Chang,Susan;Lesser,Glenn;Norden,Andrew;Cloughesy,Timothy;Olson,Jeffrey;Kerstetter-Fogle,Amber;Rich,Jeremy;Fisher,Joy;Desideri,Serena;Takebe,Naoko;Timmer,William;Grossman,
目的胶质瘤的发生和胶质母细胞瘤的耐药是由胶质瘤干细胞（GSC）介导的。有证据表明，SHH信号促进GSC增殖和自我renewal.MethodsABTC-0904是一个双臂，多中心0/II期研究GDC-0449，口服Smoothened（SMO）的抑制剂在患者接受切除复发GBM。所有患者（第I组和第II组）均接受了手术并在术后接受了药物治疗。仅I组患者在手术前接受药物治疗。主要目的是确定6个月无进展生存期（PFS-6）。次要终点包括中位PFS（mPFS）和总生存期（mOS）、有效率和毒性反应，相关研究包括GDC-0449的生物学分析、SHH信号抑制、GSC增殖和自我更新。GDC-0449在血浆中的药代动力学在75%的患者中显示出在预期治疗范围内的水平。与组II（术前无药物）相比，在GDC-0449治疗后，组I中产生⑶ 133+神经球的肿瘤细胞的比例、神经球增殖、自我更新和SHh下游信号传导的表达显著降低（分别为p <0.005; p < 0.001）。治疗耐受性良好。两组均无客观缓解者，总体PFS-6为2.4%（95% CI 0.9-11.1%）。中位PFS为2.3个月（95%CI 1.9-2.6），mOS为7.8个月（95%CI 5.4-10.1）。结论GDC-0449耐受性良好，可达到肿瘤，并抑制CD 133+神经球形成，但作为单一药物在rGBM中的临床疗效甚微。这表明rGBM的生长和维持不仅仅依赖于SHH途径，因此靶向SMO可能需要组合方法。
PurposeGliomagenesis and resistance of glioblastoma (GBM) are believed to be mediated by glioma stem cells (GSC). Evidence suggests that SHH signaling promotes GSC proliferation and self-renewal.MethodsABTC-0904 was a two-arm, multicenter phase 0/II study of GDC-0449, an oral inhibitor of Smoothened (SMO) in patients undergoing resection for recurrent GBM. All patients (Arms I and II) had surgery and received drug post-operatively. Only patients in Arm I received drug prior to surgery. Theprimary objectivewas to determine 6-month progression free survival (PFS-6). Secondary endpoints include median PFS (mPFS) and overall survival (mOS), response rate, and toxicity.Correlative studiesincluded bioanalysis of GDC-0449, and inhibition of SHH signaling, GSC proliferation and self-renewal.ResultsForty-one patients were enrolled. Pharmacokinetics of GDC-0449 in plasma demonstrated levels within expected therapeutic range in 75% of patients. The proportion of tumorcells producing CD133+neurospheres, neurosphere proliferation, self-renewal, and expression of the SHh downstream signaling was significantly decreased in Arm I following GDC-0449 treatment (p < 0.005; p < 0.001 respectively) compared to Arm II (no drug pre-op). Treatment was well tolerated. There were no objective responders in either arm. Overall PFS-6 was 2.4% (95% CI 0.9–11.1%). Median PFS was 2.3 months (95% CI 1.9–2.6) and mOS was 7.8 months (95% CI 5.4–10.1).ConclusionsGDC-0449 was well tolerated, reached tumor, and inhibited CD133+neurosphere formation, but had little clinical efficacy as a single agent in rGBM. This suggests growth and maintenance of rGBM is not solely dependent on the SHH pathway thus targeting SMO may require combined approaches.